Autosomal dominant polycystic kidney disease (ADPKD) is a frequently inherited kidney disorder with a gene frequency of 1 in 500 to 1,000 births affecting nearly 600,000 Americans and as many as 12 million people worldwide. This potentially lethal genetic disease is characterized by the formation of cysts in ductal organs, principally the kidneys and liver, in addition to extra-renal manifestations, such as vascular aneurysms and cardiac valve defects. In ADPKD, aberrant growth of tubule epithelial cells leads to the formation of innumerous fluid-filled cysts that cause massively enlarged kidneys that reach 4-8 times normal size and progressive decline in renal function. Although cysts are benign neoplasms, they ultimately cause renal insufficiency through extensive nephron loss and replacement of adjacent parenchyma with fibrosis. Currently, there is no approved clinical therapy directed at the cellular defect that is responsible for ADPKD.
In ADPKD, elevated mTOR activity contributes to the aberrant proliferation of cyst-lining epithelial cells. Stimulation of AMP-activated protein kinase (AMPK), an energy sensor that regulates cell growth, inhibits mTOR signaling and cell proliferation. AMPK also phosphorylates CFTR Cl− channels and inhibits Cl−-dependent fluid secretion. Recently, AMPK activation was shown to inhibit mTOR and cyst growth in PKD animals. Liver kinase B1 (LKB1) is a tumor suppressor that directly phosphorylates and activates AMPK; and mutations that cause a loss-of-function of LKB1 are associated with elevated mTOR activity and cancer.
Accordingly, it would be beneficial to have a compound that can provide AMPK stimulation, can function as an LKB1 activator, and that can inhibit Cl− secretion and mTOR-mediated proliferation of human ADPKD cells.